3197 – UNDERSTANDING AND TARGETING ASPARTATE METABOLISM IN THE LEUKEMIC NICHE

Bone marrow stromal cells support acute myeloid leukemia (AML) cells and protect them from cytotoxic therapies. Previously, we showed that chemoresistant AML cells undergo metabolic reprogramming characterized by increased pyrimidine synthesis, potentially fueled by aspartate provided by stromal cells. To test the therapeutic relevance, we focused on the aspartate/glutamate transporter SLC1A3. Expression of SLC1A3 was found across AML cell lines and in patient databases, with the highest expression in M4 and M5 subtypes. AML cells were sensitive to SLC1A3 inhibitors in culture, but metabolomics and rescue experiments revealed no link with aspartate or glutamate depletion. In addition, culturing cells in aspartate-free medium did not impact AML cell viability or growth. In vivo, SLC1A3 inhibitors increased bone marrow aspartate levels, but did not affect AML growth. Current efforts are focused on assessing the metabolic role of SLC1A3 in AML, and understanding how AML cells obtain aspartate in the bone marrow. Bone marrow stromal cells support acute myeloid leukemia (AML) cells and protect them from cytotoxic therapies. Previously, we showed that chemoresistant AML cells undergo metabolic reprogramming characterized by increased pyrimidine synthesis, potentially fueled by aspartate provided by stromal cells. To test the therapeutic relevance, we focused on the aspartate/glutamate transporter SLC1A3. Expression of SLC1A3 was found across AML cell lines and in patient databases, with the highest expression in M4 and M5 subtypes. AML cells were sensitive to SLC1A3 inhibitors in culture, but metabolomics and rescue experiments revealed no link with aspartate or glutamate depletion. In addition, culturing cells in aspartate-free medium did not impact AML cell viability or growth. In vivo, SLC1A3 inhibitors increased bone marrow aspartate levels, but did not affect AML growth. Current efforts are focused on assessing the metabolic role of SLC1A3 in AML, and understanding how AML cells obtain aspartate in the bone marrow.